CardioBrief: After Yet Another Failure, Stem Cell Leaders Double Down

Could repeated doses of stem cells break the string of negative trials?

Despite an unrelieved history of negative trials, stem cell leaders continue to defend their field.

In response to the failure of yet another cardiac stem clinical trial, Roberto Bolli, a prominent leader in the field, argued that it's time for a "paradigm shift" in the field. We need more stem cell therapy, not less, he argued, perhaps counterintuitively, in an article in Circulation Research. Bolli, who is also the editor-in-chief of the journal, proposed the novel position that the single dose of cells used in virtually all previous stem cell therapy trials should be replaced down the road with repeated doses of stem cells.

It is an understatement to say that cardiac stem cell therapy has not lived up to earlier expectations and hype. As Bolli himself wrote in his article, "a rising tide of skepticism has bedeviled the field" and "enthusiasm for cell therapy has been dampened by the inconsistent, modest, borderline, or undetectable benefits reported in clinical trials." He noted that "no cell-based therapy is close to being approved for heart disease" and "leading some critics even to question whether clinical studies should continue."

Bolli rejected this grim view of the field. His response was to double down on stem cells, writing that "just as most pharmacologic agents are ineffective when given once but can be highly effective when given repeatedly, so a cell product may be ineffective, or modestly effective, when given as a single treatment, but may turn out to be quite efficacious if given repeatedly. This concept constitutes a major paradigm shift, with potentially vast implications for the entire field of reparative medicine."

Bolli wrote that the single-dose model was based on the initial hope that "transplanted cells would engraft and differentiate into cardiac cells." As it turns out, "we now know that the vast majority of transplanted cells disappear quickly, regardless of the number that is administered."

The new concept is that "transplanted cells impart their salubrious effects not by engrafting, but by releasing EVs [extracellular vesicle](or other paracrine factors) into the surrounding tissue." However, as critics have pointed out, there is no consensus on the existence of this "salubrious effect," since these have only emerged in secondary or post hoc analyses. Further, there is no agreement or detailed elucidation of a biologically-plausible mechanism for this effect.

One reason multiple dosing hasn't been attempted in the past, even in rodents, is "because the stress of repeated thoracotomies is associated with prohibitively high mortality and because most Animal Committees would not approve such protocols," Bolli stated. Now that cells can be delivered percutaneously, Bolli argued, it may be feasible to study multiple doses in animals and in humans.

Bolli didn't dwell on it, but one implication here is that human trials would require patients to undergo multiple percutaneous procedures. But this would almost certainly raise a whole host of new issues. What are the ethical issues of performing multiple invasive procedures on patients of an entirely unproven therapy? Further, even if it proved successful, what would be the cost of multiple invasive procedures requiring expensive cell isolation and preparation techniques?

Circling The Wagons

Bolli's paper accompanied the publication in Circulation Research of PreSERVE-AMI, a highly anticipated (in the stem cell field, at least) trial "to evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI." To cut to the chase, no safety issues emerged but there was no difference in the primary endpoint of the trial, which was change in resting myocardial perfusion over 6 months.

But, like Bolli, the trial investigators managed to find a ray of hope. There were three deaths in the trial, all in the control arm. And, in a secondary analysis, "when adjusted for time of ischemia, a consistently favorable cell dose–dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05)."

These findings led the investigators to conclude that the trial "provides evidence supporting safety and potential efficacy." This rosy view of the trial gained support in a second editorial about the trial, written by a group of stem cell researchers at the University of Miami led by another prominent leader in the field, Joshua Hare. Despite the main results, "the positive post hoc analyses from this trial will undoubtedly lead to important new hypotheses to be tested in future trials," they wrote.

Searching For The Pony

Bolli's proposal can be viewed as a desperate Hail Mary effort to salvage a dying -- or, some would say, already dead -- field of research. But if all the failures are due to single dosing then the entire fields gets a do-over.

"If one dose is not sufficient to evaluate efficacy, then the conclusions of these studies, particularly those that have reported 'negative' results, could be questioned because the benefits of the treatment may have been underestimated or even completely overlooked," he wrote. "Disquietingly, an entire body of literature (almost all studies conducted to date) may have to be reconsidered." But, of course, there's no concrete evidence that repeated doses will result in a different outcome.

Bolli wondered if the negative results were "because the product did not work or because the treatment protocol was inadequate?" But Bolli, along with the trial investigators and the other editorialists, failed to seriously consider the more plausible explanation that the repeated and consistent failures indicate that stem cell therapy is just not ready for prime time. These researchers are like the boy in the proverbial stable, frantically shovelling out an enormous pile of manure. When asked why he's working so hard he explains, "There must be a pony here somewhere!"

Perhaps it's about time for cardiac stem cell researchers to admit there's no pony.

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